Operant Analysis of Behavior Associated With Oral Self-Administration Of Drug Solutions in RatsDigitalCommons@URI DigitalCommons@URI
Operant Analysis of Behavior Associated With Oral Self-Operant Analysis of Behavior Associated With Oral Self-
Administration Of Drug Solutions in Rats Administration Of Drug Solutions in Rats
Joseph David Zabik University of Rhode Island
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Recommended Citation Recommended Citation Zabik, Joseph David, "Operant Analysis of Behavior Associated With Oral Self-Administration Of Drug Solutions in Rats" (1974). Open Access Dissertations. Paper 170. https://digitalcommons.uri.edu/oa_diss/170
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SEi.:F-ADHD:IS'I'RATlON OF DRUG SOLUTIONS I N RATS
BY
OF THE REQUIREHENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY
UNIVERSITY OF RHODE ISLAi.'ID
1974
ABSTRACT
Since many drugs which are abused by man are taken ora11y. it was
desirable tc develop a method s11itable to quantitatively and reli ably I
measure oral self-administration of drugs and their effects on behavior
in experimental animals.
Water deprived rats were trained to 1 ick for drug solutions (4.34
ul/lick) and bar press for food on a Fixed Interval (FI) 60 second
schedule and press another bar for secondary reinforcements on a Fixed
Ratio (FR )-5 schedule as three concurrent operants. Non-discriminated
responding was inconsequential. An appropr~ate drug solution was sub­
stituted for water or the drugs were injected intraperitoneally before
the session. for each drug, a dose-response was determined with usually
six replicate sessions per dose for each rat. Three rats were usually
used in each study.
Substitution of solutions of amphetamine (0.5, 0.99 and 1.99 m
Molar) resulted in concentration dependent decreases in discriminated
and non-discriminated licking , and discriminated lever pressing for
secondary reinforcement. Non-discriminated lever pressing for second-
ary reinforcement or food pellets increased. Consequential lever ~ress -
ing for food pellets was unaffected. The effects of amphetamine on
lever pressing and licking were similar whether an acute injection was
made before the session or amphetamine was self-ingested during the
session.
Chronic injections of amphetamine (5 mg/kg, I.P., 18 hours before
the water session, given daily for 5 days prior to the study_ and during
the study for 30 days) resulted in an increased sensitivity to ingested
amphetamine . This increased sensitivity was manifested by a shift of
-i-
concentration respon~e Guryes to lower concentrations l0.125, 0.25, 0.50
m Molar}.
(0.5 mM or 1.0 mM).
Substitution of solutions of ethanol (10, 20, 40, 80% v/v) re-
sulted in concentration dependent decreased in discriminated and non­
qiscriminated licking, and discriminated lever pressing for secondary
reinforcement. Non-discriminated lever pressing for secondary rein­
forcement or food pellets was increased. Consequential lever pressing
for food pellets was unaffected. While the licking rate decreased
with increased concentrations of ethanol, the grams of absolute ethanol
ingested increased. The effects of oral injections of ethanol (12 ml/
kg, of a 50% v/y solution, 15 minutes before the session on behavior
were similar to the effects of ingested ethanol except for a decrease . in number of food pellets obtained.
Disulfiram (50 mg/kg, I.P., 60 minutes before the ethanol session)
did not affect behaviors for various contingencies during water sessions
or initial portions of ethanol (20% v/v) sessions. However, disulfiram
pretreatment depressed behaviors completely after the inital ingestion
of small quar.tities of ethanol.
Rats were given increasing doses of morphine sulfate, until a total
daily dose of 200 mg/kg was attained.
Oeprivation of these rats of their daily morphine for four succes­
sive days had little effect on water licking, but licking rates for a
solution of amphetamine (0.5 m Molar) decreased dur1ng the abstinence
while licking rates for a solution of ethanol (80% v/v) remained con-
. -ii-
sistently higher than thos.e for amphetamine. Nal orphine (_4 mg/k~ abol-,
ished licking for water in three of four rats. indi.cating a difference
between nalorphine ind~ced and abstinence induced withdrawal .
. -iii.-
ACKNOWLEDGEMENTS
The author wishes to express his gratitude to Dr. Harbans Lal, his
major professor, for his guidance and endless patience tl1roughout the
study and in the preparation of this thesis. Special thanks are also
conveyed to Dr. Harbans Lal for his part in the shaping of the author's
attitude and ability which are essential for a career in research.
The author wishes to express his gratitude to the members of his
graduate committee for their guidance in the preparation of this thesis.
The author wishes to express his gratitude to Anne Partenhei mer
and Pamela Brink for the typing of this thesis.
The author a 1 so \'fishes to convey his thanks to his fe 11 ow students
for their suggestions during these studies and to all the others who
have been so helpful in all phases of the preparation of this thesis.
The author' is grateful to the University of Rhode Island for · pro­
viding financial assistance during these studies.
-iv-
DEDICATION
The author would li ke to dedicate this thesis to his wife, Regina, I
without whose constant encouragement, confidence and prayers this thesis
could not have been possible.
-v~
EXPERIMENTAL.................................................... 26
MATERIALS ........................•.•.......................... 26
SUBJECTS................................................... 26
APPARATUS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . • . . . . 26
DRUGS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
PROCEDURE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . • . . . . . . . . . . . . . . . . . . . . 26
STATISTICAL METHODS........................................ 35
TABLE PAGE
1 DETERMINATION OF VOLUME OF DROPS DELIVERED FROM LICKING OPERANDUM . . . .................................... 28
2 EFFECT OF AMPHETAMINE SELF··INGESTION ON CONSE- QUENTIAL LICKING RATE UNDER SELF-PRODUCED (SPS) AND PROGRAMMED (PS) STIMULUS IN NORMAL RATS Z-29, 30' 33 ..................................... . ............ 46
3 EFFECT OF AMPHETAMINE SELF-INGESTION ON TIME IN MINUTES SPENT IN CONSEQUENTIAL LICKING UNDER SELF- PRODUCED (SPS) AND PROGRAMMED (PS) STIMULUS IN NORMAL RATS Z-29, 30, 33 ... . ............................ 48
4 DROPS OF FLUID DELIVERED DURING AMPHETAMINE SELF- INGESTION UNDER SELF-PRODUCED (SPS) AND PROGRAMMED (PS) STI MULUS IN NORMAL RATS Z-29, 30, 33 ............... 51
5 DOSE OF AMPHETAMINE (MG) DELIVERED DURING SELF- INGESTION UNDER SELF-PRODUCED (SPS) AND PROGRAMMED (SP) STIMULUS IN NORMAL RATS Z-29, 30, 33 ............... 54
6. EFFECT OF AMPHETAMINE SELF-INGESTION ON INCONSEQUEN- TIAL LICKING RATE ur·mER SELF-PRODUCED STIMULUS (SPS) IN NORMAL RATS Z-29, 30, 33 .............•... . ..... 56
7 EFFECT OF AMPHETAMINE SELF-INGESTION ON CONSEQUEN- TIAL LEFT LEVER PRESSING FOR SECONDARY REINFORCE- MENT UNDER SELF-PRODUCED STIMULUS (SPS) IN NORMAL RATS Z-29, 30, 33 ...................•................... 59
8 EFFECT OF AMPHETAMINE SELF-INGESTION ON INCONSEQUEN- TIAL LEFT LEVER PRESSING FOR SECONDARY REINFORCE- MENT UNDER SELF-PRODUCED (SPS) AND PROGRAMMED (PS) STIMULUS IN NORMAL RATS Z-20, 30, 33 ............... 62
9 EFFECT OF AMPHETAMINE SELF-INGESTION ON CONSEQUEN- TIAL LICKING RATE UNDER SELF-PRODUCED (SPS) AND PROGRAMMED (PS) STIMULUS IN CHRONICALLY INJECTED RATS Z-29, 30, 33 ....................................... 67
10 EFFECT OF AMPHETAMINE SELF-INGESTION ON TIME IN MINUTES SPENT IN CONSEQUENTIAL LICKING UNDER SELF- PRODUCED (SPS) AND PROGRAMMED (PS) STIMULUS IN
70 · CHRONICALLY INJECTED RATS Z-29, 30, 33 ..................
11 DOSE OF AMPHET/lJ1INE (MG) DELIVERED DURING SELF- INGESTION UNDER SELF-PRODUCED (SPS) ANO PROGR~~MED (PS) STIMULUS IN CHRONICALLY INJECTED RATS Z-29,
74 30 ,33 ...................................................
LIST OF TABLES
TABLE PAGE
12 EFFECT OF AMPHETAMINE SELF-INGESTION ON INCONSEQUEN- TIAL LICKING RATE UNDER SELF-PRODUCED STIMULUS (SPS) IN CHRONICALLY INJECTED RATS Z-29, 30, 33 ............... 77
13 EFFECT OF AMPHETAMINE SELF-INGESTION ON CONSEQUEN- TIAL LEFT LEVER PRESSING FOR SECONDARY REINFORCE- MENT UNDER SELF-PRODUCED STIMULUS (SPS) IN CHRON- ICALLY INJECTED RATS Z-29, 30, 33 ................. .' ..... 80
14. EFFECT OF AMPHETAMINE SELF-INGESTION ON INCONSEQUEN- TIAL LEFT LEVER PRESSING FOR SECONDARY REINFORCE- MENT UNDER SELF-PRODUCED (SPS) AND PROGRAMMED (PS) STIMULUS IN NORMAL RATS Z-29, 30, 33 .................... 83
15 EFFECT OF DAILY AMPHETAMINE INJECTION ON DURATION OF BARBITURATE NARCOSIS ................................. 86
16 EFFECT OF CHLORPROMAZINE PRETREATMENT ON SUBSEQUENT AMPHETAMINE SELF-INGESTION .............................. 87
17 EFFECT CF AMPHETAMINE SELF-INGESTION ON CONSEQUtN- TIAL LICKING RATE UNDER SELF-PRODUCED (SPS) AND PROGRAMMED (PS) STI MUL US IN RATS Z-34, 35, 37, WITH FOOD PELLETS AVAILABLE ............................. 90
18 MILLIGRAMS OF AMPHETAMINE DELIVERED DURING AMPHETA- MINE INGESTION UNDER SELF-PRODUCED (SPS) AND PRO- GRAMMED (PS) STI MULUS IN RATS Z-34, 35, 37 WITH FOOD PELLETS AVAILABLE .................................. 93
19 EFFECT OF AMPHETAMINE SELF-INGEST-ION ON TIME IN MINUTES SPENT IN CONSEQUENTIAL LICKING UNDER SELF- PRODUCED (SPS) AND PROGRAMMED STIMULUS IN RATS Z-34,
95 35, 37 WITH FOOD PELLETS AVAILABLE. .....................
20 DROPS OF FLUID DELIVERED DURING AMPHETAMINE SELF- INGESTION UNDER SELF-PRODUCED (SPS) AND PROGRAMMED (PS) STIMULUS IN RATS Z-34, 35, 37 WITH FOOD PELLETS AVAILABLE ....................................... 98
21 EFFECT OF AMPHETAMINE SELF-INGESTION ON INCONSEQUEN- TIAL LICKING RATE UNDER SELF-PRODUCED (SPS) STIM- ULUS IN RATS Z-34, 35 37 WITH FOOD PELLETS AVAIL- ABLE . ................................................. · · 101
LIST OF TABLES
TABLE PAGE
22 EFFECT OF AMPHETAMINE SELF-INGESTIOM ON CONSEQUEN- TIAL LEFT LEVER PRESSING FOR SECONDARY REINFORCE- MENT UNDER SELF-PRODUCED (SPS) STIMULUS IN RATS Z-34, 35, 37 WITH FOOD PELLETS .......................... 104
23 EFFECT OF AMPHETAMINE SELF-INGESTION ON INCONSE- QUENTIAL LEFT LEVER PRESSING FOR SECONDARY REIN- FORCEMENT UNDER SELF-PRODUCED (SPS) AND PROGRAMMED (PS) STI MULUS IN RATS Z-34, 35, 37 WITH FOOD PELLETS AVAILABLE ............................................... l 07
24 EFFECT OF AMPHETAMINE ON RIGHT LEVER PRESSING FOR FOOD PELLETS UNDER SELF-PRODUCED (SPS) AND PRO- GRAMMED (PS) STIMULUS IN RATS Z-34, 35, 37 .............. 110
25 EFFECT OF AMPHETAMINE SELF-INGESTION ON CONSEQUENTIAL RIGHT LEVER PRESSI NG FOR FOOD PELLETS UNDER SELF- PRODUCED (SPS) AND PROGRAMM ED (PS) STIMULUS IN RATS Z- 34 , 3 5 , 3 7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
26 EFFECT OF AMPHETAMINE INJECTION ON CONSEQUENTIAL LICKING RATE UNDER SELF-PRODUCED (SPS) AND PRO- GRAMMED (PS) STI MU LUS IN NORMAL RATS Z-19, 20, 22 ....... 117
27 EFFECT OF AMPHETAMINE INJECTION ON TIME IN MINUTES SPENT IN CONSEQUENTIAL LICKING UNDER SELF-PRODUCED (SPS) AND PROGRAMMED (PS) STIMULUS IN NORMAL RATS
120 Z-19, 20, 22 ............................................
28 EFFECT OF AMPHETAMINE INJECTION ON DROPS OF FLUID DELIVERED UNDER SELF-PRODUCED (SPS) AND PROGRAMMED
123 (PS) STI MU LUS IN NORMAL RATS Z-19, 20, 22 ...............
29 EFFECT OF AMPHETAMINE INJECTION ON CONSEQUENTIAL LICKING RATE UNDER SELF-PRODUCED (SPS) STIMULUS
125 IN NORMAL RATS Z-19, 20, 22 .............................
30 EFFECT OF AMPHETAMINE INJECTION ON CONSEQUENTIAL LEFT LEVER PRESSING FOR SECO NDARY REINFORCEMENT UNDER SELF-PRODUCED (SPS) STIMULUS IN N0~1AL RATS
128 Z-19, 20, 22 ............................................
31 EFFECT OF AMPHETAMINE INJECTION .ON INCONSEQUENT IAL LEFT LEVER PRESSING FOR SECONDARY REINFORCEMENT UNDER SELF-PRODUCED (SPS) AND PROGRAMMED (PS)
130 STIMULUS IN NORMAL RATS Z-19, 20, 22 ....................
U5T OF TABLES
TABLE PAGE
32 EFFECT OF ETHANOL SELF-INJECTION ON CONSEQUENTIAL LICK- ING RATE UNDER SELF-PRODUCED (SPS) AND PROGRAMMED (PS) STIMULUS IN NORMAL RP.TS Z-25, 26, 27, 28 ........... 134
33 EFFECT OF ETHANOL SELF-INGESTION ON TIME IN MINUTES SPENT IN CONSEQUENTIAL LICKING UNDER SELF-PRODUCED (SPS) ANO PROGRAMMED (PS) STIMULUS IN RATS Z-25, 26,
137 27, 28 ..................................................
34 DROPS OF FLUID DELIVERED DURING ETHANOL SELF-INGES- TION UND ER SEL F-PRODUCED (SPS) AND PROGRAMMED (PS)
141 STIMULUS IN RATS Z-25, 26, 27, 28 .......................
35 GRAMS OF ABSOLUTE ETHANOL INGESTED UNDER SELF- PRODUCED (SPS) AND PROGRAMMED (PS) STIMULUS IN
144 RATS Z-25, 26, 27, 28 ...................................
36 EFFECT OF ETHANOL SELF-INGESTION ON INCONSEQUENTIAL LICKING RATE UNDER SELF-PRODUCED (SPS) STIMULUS
149 IN RATS Z-25, 26, 27, 28 ................................
37 EFFECT OF ETHANOL SELF-INGESTION ON CONSEQUENTIAL LEFT LEVER PRESSING FOR SECONDARY REINFORCEMENT UNDER SELF-PRODUCED (SPS) STIMULUS IN RATS Z-25,
152 26, 27' 28 .............................................. '
38 EFFECT OF ETHANOL SELF-INGESTION ON LEFT LEVER PRESSING FOR SECONDARY REINFORCEMENT UNDER SELF- PRODUCED (SPS) AND PROGRAMMED (PS) STIMULUS IN
156 RATS Z-25, 26, 27, 28 ...................................
39 EFFECT OF ETHANOL SELF-INGESTION ON CONSEQUENTIAL LICKING RATE DURING SELF-PRODUCED (SPS) AND PRO- GRAMMED (PS) STIMULUS IN RATS Z-41, 42, 43, WITH
159 FOOD PELLETS AVAILABLE ..................................
40 EFFECT OF ETHANOL SELF-INGESTION ON TIME IN MINUTES SPENT IN CONSEQUENTIAL LICKING UNDER SELF-PRODUCED (SPS) AND PROGRAMMED (PS) stimulus in rats Z-41,
162 42, 43 WITH FOOD PELLETS AVAILABLE. .....................
41 DROPS OF FLUID DELIVERED DURING ETHANOL SELF-INGESTION UNDER SELF-PRODUCED (SPS) ANO PROGRAMMED (PS) STIMULUS IN RATS Z-41, 42, 43 WITH FOOD PELLETS
164 AVAILABLE ............................................... ··
42 GRAMS OF ETHANOL INGESTED UNDER SELF-PRODUCED (SPS) AND PROGRAMMED (PS) STIMULUS IN RATS Z-41, 42, 43
167 WITH FOOD PELLETS AVAILABLE ............•................
LIST OF TABLES
TABLE PAGE
43 EFFECT OF ETHANOL SELF-INGESTION ON INCONSEQUEN- · TIAL LICKING RATE UNDER SELF-PRODUCED STIMULUS (SPS) IN RATS Z-41, 42, 43 WITH FOOD PELLETS AVAILABLE............................................... 170
44 EFFECT OF ETHANOL SELF-INGESTION ON CONSEQUEN- TIAL LEFT LEVER PRESSING FOR SECO NDARY REINFORCE­ MENT DURING SELF-PRODUCED STIMULUS (SPS) IN RATS Z-41, 42, 43 WITH FOOD PELLETS AVAILABLE ........... 172
45
46
EFFECT OF ETHANOL SELF-INGESTION ON INCONSEQUENTIAL LEFT LEVER PRESSING FOR SECONDARY REINFORCEMENT DURING SELF-PRODUCED (SPS) AND PROGRAMMED STIM- ULUS (PS) IN RATS Z-41, 42, 43 WITH FOOD PELLETS AVAILABLE ............................................ ; ..
EFFECT OF ETHANOL SELF-INGESTION ON RIGHT LEVER PRESSING FOR FOOD PELLETS (DURING SELF-PRODUCED (SPS) AND PROGRAMMED (PS) STIMULUS) IN RATS Z-41, 42 ' 43 ••.••••..•••••••....•..••••••.••.•••••••.••.••..••
47 EFFECT OF ETHANOL SELF-INGESTION ON CONSEQUENTIAL
175
177
RIGHT LEVER RATE FOR FOOD PELLETS UNDER SELF­ PROOUCED (SPS) AND PROGRAMMED (PS) STIMULUS IN RATS Z-41, 42, 43 ....................................... 180
48
49
50
51
EFFECT OF SELF-INGESTION OF WATER AND ETHANOL (40%, V/V). COMBINED DATA FOR RATS Z-53, Z-54, Z-55, IS EXPRESSED AS MEANS, STANDARD ERROR AND TOTAL NUMBER OF SESSIONS ............................... .
EFFECTS OF ORAL INJECTIO NS OF ETHANOL (12 ML/KG, OF A 50% V /V SOLUTION, 15 MINUTE PRETREATMENT) ON SELF-INGESTION OF WATER. COMBINED DATA FOR RATS Z-53, Z-54, Z-55 IS EXPRESSED AS MEANS, STANDARD ERROR AND TOTAL NUMBER OF SESSIONS ..................... .
EFFECTS OF ORAL INJECTIONS OF ETHANOL (12 ML/KG, OF A 50% V/V SOLUTION, 15 MINUTt PRETREATMENT) ON SELF­ INGESTION OF ETHANOL (40% V/V). COMBINED DATA FOR RATS Z-53, Z-54, Z-55 IS EXPRESSED AS MEANS, STAN- DARD ERROR, AND TOTAL NUMBER OF SESSIONS ...........•....
EFFECTS OF ORAL INJECTIONS OF ETHANOL (12 ML/KG, OF A 50% V/V SOLUTION, 15 MINUTE PRETREATMENT) ON SELF­ INGESTION OF ETHANOL (40% V/V) ANO WATER. COMBINED DATA FOR RATS Z-53, Z-54, Z-55 IS EXPRESSED AS MEANS, STANDARD ERROR ANO TOTAL SESSIONS ...................... .
183
185
188
190
TABLE PAGE
52 EFFECT OF NALORPHINE PRETREATMENT (4 MG/KG, I.P., 60 MINUTES PRIOR TO SESSION) ON BEHAVIOR (RESPONSES/ MINUTE) IN RATS Z-44, Z-45, Z-47, Z-49 WHICH WERE CHRONICALLY RECEIVING DAILY INJECTIONS OF MORPHINE (200 MG/KG, I.P.) ........•.... .. ......................... 203
LIST OF FIGURES
2 REPRESENTATION OF SCHEDULES ............................•. 29
3 ACQUISITION TO LICKING FOR WATER IN A NAIVE RAT .......... 31
4 TYPICAL CUMULATIVE RECORD WITH LABELED COMPONENTS ........ 33
5 EFFECT OF SELF-INGESTION OF AMPHETAMINE ON LICKING RATE AND LEVER PRESSING IN RAT Z-19. DAILY PRE­ DRUG (WATER) SESSION ARE ON LEFT WITH CORRESPOND­ ING AMPHETAMINE SESSION ON THE RIGHT. COMPLETE EXPLANATION OF THE CUMULATIVE RECORDS IS PRESENTED IN FIGURE 4............................................ 43
6 EFFECT OF AMPHETAMINE SELF-INGESTION ON CONSEQUEN- TIAL LICKING RATE UNDER SELF-PRODUCED AND PRO­ GRAMMED STIMULUS IN RATS Z-29, Z-30, Z-33. CLEAR SQUARES REPRESENT SIGNIFICANT DIFFERENCES (P<0.05) BETWEEN AMPHETAMINE SESSION AND CORRESPONDING PREDRUG SESSIONS (CIRCLES) ............................. 45
7 EFFECT OF AMPHETAMINE SELF-INGESTION ON DISCRIMIN- ATED AND NON-DISCRIMINATED LEFT LEVER PRESSING RATE (AMPHETAMINE/PREORUG) FOR SECONDARY REINFORCE­ MENT DURING SELF-PRODUCED STIMULUS SEGMENTS IN RATS Z-29, Z-30, Z-33. SHADED AREAS REPRESENT SESSIONS WHERE AMPHETAMINE WAS INGESTED ................ 61
8 EFFECT OF AMPHETAMINE SELF-INGESTION ON CONSEQUEN- TIAL LICKING RATE UNDER SELF-PRODUCED AND PROGRAMMED STIMULUS IN RATS Z-29, Z-30, Z-33 WHICH WERE CHRON­ ICALLY INJECTED WITH 5 MG/KG, I.P. OF AMPHETAMINE, 4 HOURS AFTER THE AMPHETAMINE SESSION. CLEAR SQUARES REPRESENT SIGNIFICANT DIFFERENCE (P<0.05) BETWEEN AMPHETAMINE AND CORRESPONDING PREDRUG SESSIONS (CIRCLES)..................................... 65
9 EFFECT OF AMPHETAMINE SELF-INGESTION ON CONSEQUEN- TIAL LICKING RATE UNDER SELF-PRODUCED AND PROGRAMMED STIMULUS IN RATS Z-29, Z-30, Z-33 WHEN THEY WERE NORMAL AND AFTER CHRONIC INJECTIONS OF AMPHETAMINE ..... 66
10 EFFECT OF AMPHETAMINE SELF-INGESTION ON AMOUNT OF TIME IN MINUTES SPENT IN CONSEQUENTIAL LICKING DURING 30 MINUTE SESSIONS UNDER SELF-PRODUCED AND PROGRAMMED STIMULUS IN RATS Z-29, Z-30, Z-33, WHEN THEY WERE NORMAL AND AFTER CHRONIC . INJECTIONS OF
72 AMPHETAMINE ..........•.................................
LIST Of FIGURES
EFFECT OF AMPHETAMINE SELF-INGESTION ON AMOUNT OF AMPHETAMINE (MG) INGESTED DURING 30 MINi.JTE SES3IONS UNDER SELF-PRODUCED AND PROGRAM!v1 ED STIMULUS IN RATS Z-29, Z-30, Z-33 WHEN THEY WERE NORMAL AND AFTER CHRONIC INJECTIONS OF AMPHETAMINE .............. .
EFFECT OF AMPHETAMINE SELF-INGESTION ON DISCRIMINATED AND NON-DISCRIMINATED LEFT LEVER PRESSING RATE (AMPHETAMI NE/PREDRUG) FOR SECONDARY REINFORCE- MENT DURING SELF-PRODUCED STI MU LUS IN RAT S Z-29) Z-30, Z-33 WHICH WERE CHRONICALLY INJECTED WITH 5 MG/KG, I.P. GF AMPHETAMINE, 4 HOURS AFTER THE AMPHETAMINE SESSIONS. SHADED AREAS REPRESENT SESSIONS WHERE AMPHETAMINE WAS INGESTED .............. .
EFFECT OF AMPHETAMINE SELF-INGESTION ON AMOUNT OF AMPHETAMINE INGESTED DURING 30 MINUTE SESSIONS AND ON CONSEQUENTIAL LICKING RATE UNDER SELF­ PRODUCED AND PROGRAMMED STI MULUS IN RATS Z-34, Z-35, Z-37. FOOD PELLETS WERE CONCURRENTLY AVAILABLE ON FI-60 11 RIGHT LEVER PRESSING ............. .
EFFECT OF AMPHETAMINE SELF-INGESTION ON CONSE­ QUENTIAL AND INCONSEQUENTIAL LEFT LEVER PRESSING FOR SECONDARY REINFORCEMENT DURING SELF-PRODUCED ANO PROGRAMM ED STIMULUS IN RATS Z-34, Z-35, Z-37 . FOOD PELLETS WERE CONCURRENTLY AVAILABLE ON FI-60 11
RIGHT LEVER PRESS ING ................................. .
EFFECT OF AMPHETAMINE SELF-INGESTION ON TOTAL (CON­ SEQUENTIAL AND INCONSEQUENTIAL) AND CONSEQUENTIAL RIGHT LEVER PRESSING FOR FOOD PELLETS UNDER SELF­ PRODUCEO AND PROGRAMM ED STIMULUS IN RATS Z-34, Z-35, Z-37 . ................................................ .
EFFECT OF AMPHETAMINE INJECTION ON LICKiNG FOR WATER AND LEVER PRESSING IN RAT Z-19. DAILY PREDRUG (WATER) SESSIONS ARE ON LEFT AND CORRESPONDING AMPHETAMINE SESSIONS ARE ON RIGHT. COMPLETE EXPLANATION OF THE CUMULATIVE RECORD IS PRESENTED IN FIGURE 4 .......................................... .
EFFECT OF AMPHETAMINE INJECTION ON CONSEQUENTIAL LICKING RATES FOR WAT ER DURING SELF-PRODUCED AND PROGRAMMED STIMULUS IN RATS Z-19, Z-20, Z-22. CLEAR SQUARES INDICATE SIGNIFICANT DIFFERENCE (P 0.05} BETWEEN AMPHETAMINE SESSIONS ANO CORRES- PONDING PREORUG SESSIONS (CIRCLES) ................... .
PAGE
76
82
89
103
109
115
116
FIGURE
18 EFFECT OF ETHANOL SELF-I NGES TION ON CONSEQUENTIAL LICKING RATE DURING SELF-P RODU CED AND PROGRAMMED STIMULUS IN RATS Z-25, Z-27, Z-28. CLEAR SQUARES INDICATE SIGNIFI CANT DIFFERENCE (P<0.05) BETWEEN ETHANOL SESSIONS AND CORRESPONDING. PRE-
PAGE
DRUG (WATER) SESSIONS (CIRCLES) ....................... 133
19 EFFECT OF ETHANOL SELF-INGESTION ON MINUTES SPENT IN CONSEQUENTIAL LICKING AND GRAMS OF ABSOLUTE ETHANOL CONSUMED DURING 30 MINUTE SESSIONS UNDER SELF-PRODUCED AND PROGRAMMED STIMULUS IN RATS Z-25, Z-26, Z-27, Z-28 ................................ 148
20 EFFECT OF ETHANOL SELF-INGESTION ON DISCRIMINATED AND NON-DISCRIMI NATED LEFT LEVER PRESSING FOR SECONDARY REINFORCEMENT DURING SELF-PRODUCED STIMULUS IN RATS Z-25, Z-27, Z-28. CLEAR SQUAR ES INDICATE SIGNIF ICANT DIFFERENCE (P<0.05) BETWEEN ETHANOL SESSIONS AND CORRESPONDING PREDRUG WATER SESSIONS (CIRCLES).................................... 154
21 EFFECT OF DISULFIRAM INJECTION (50 MG/KG, I.P.) GIVEN 60 MINUTES BEFORE ALCOHOL SESSION, ON SELF­ INGESTION OF ALCOHOL (20% V/V) DURING 60 MINUTE SESSIONS IN RATS Z-59, Z-60, Z-61. CUMULATIVE RECORDS ON THE LEFT ARE PREDRUG AND ALCOHOL SESSIO NS WITHOUT DISULFIRAM, AND RECORDS ON THE RIGHT ARE THE ALCOHOL SESSIONS AFTER DISULFIRAM PRETREATMENT, ALONG WITH PREDRUG SESSION. COM­ PLETE EXPLANATION OF THE CUMULATIVE RECORDS IS PRESENTED IN FIGURE 4 .............. ·................... 192
22 EFFECT OF DISULFIRAM (50 MG/KG, I.P ) ON DROPS OF ETHANOL (20% V/V) CONSUMED DURING 60 MINUTE SESS­ IONS (LOWER HALF OF FIGURE) IN RATS Z-59, Z-60, Z-61. DAY 1 IS LAST SESSION BEFORE DISULFIRAM, DAYS 2-7 ARE CONSECUTIVE DAYS OF DISULFIRAM TREAT­ MENT, DAYS 8-10 ARE CONSECUTIVE DAYS FOLLOWING DI­ SULFIRAM TREATMENT. CORRESPONDING PREDRUG (WAT ER) SESSIO NS (30 MINUT ES) ARE PRESENTED IN UPPER HALF OF FIGURE .. ........................................... 194
23 EFFECT OF WITHHOLDING DAILY MORPHINE INJECTION (200 MG/KG, I.P.) FOR FOUR CONSECUTIVE DAYS ON CONSE- QUENTIAL LICKIN°G RATES FOR WATER AND AMPHETAMINE ..... ·. 196
LIST OF FIGURES
FIGURE PAG,f
24 EFFECT OF WITHHOLDING DAILY MORPHINE INJECTION (200 MG/KG, I.PJ FOR FOUR CO lSECUTIVE DAYS ON CONSE­ QUENTIAL LICKING RATES FOR WATER, AMPHETAMINE (0.5 mM) AND ALCOHOL (80% V/V} UNDER SELF-PRODUCED AND PROGRAMMED STI MU LUS IN MORPHINE DEPENDENT RATS Z-47 AND Z-49. FOOD PELLETS WERE CONCURRENTLY AVAILABLE ON FI-60 11 RIGHT LEVER PRESSING ................ 197
25 EFFECT OF WITHHOLDING DAILY MORPHINE INJECTION (200 MG/KG, I.P.) FOR FOUR CONSECUTIVE DAYS ON MINUTES SPENT IN CONSEQUENTIAL LICKING FOR WATER AND AMPHE­ TAMINE (0.5 mM) UNDER SELF-PRODUCED AND PROGRAMMED STIMULUS IN MORPHINE DEPENDENT RATS Z-49 AND Z-45 ........ 198
26 EFFECT OF WITHHOLDING DAILY MORPHINE INJECTION (200 MG/KG, I.P.l FOR FOUR CONSECUTIVE DAYS ON MINUTES SPENT IN CONSEQUENTIAL LICKING FOR WATER, AMPHE­ TAMINE (_0.5 mM) AND ALCOHOL (80% V/V) UNGER SELF­ PRODUCED ANO PROGRAMM ED STIMULUS IN MORPHINE DE­ PENDENT RATS Z-47 AND Z-49. FOOD PELLETS WERE CONCURRENTLY AVA! LAB LE ON F I-60 11 RIGHT LEVER PRESS I NG. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 99
2.7 TOP-EFFECT OF FIRST DAY OF ~IITHDRAWAL OF DAILY
28
MORPHINE INJECTION (200 MG/KG) ON WATER INGESTION (LEFT SIDE) AND AMPHETAMINE (0.5 mM) INGESTION (RIGHT SIDE) IN MORPHINE DEPENDENT RAT Z-49.
CENTER-EFFECT OF FIRST DAY OF WITHDRAWAL OF DAILY .MORPHINE INJECTION (200 MG/KG) ON WATER INGESTION (LEFT SIDE) AND ALCOHOL (80% V/V) INGESTION (RIGHT SIDE) IN MORPHINE DEPENDENT RAT Z-49.
BOTTON-EFFECT OF SECOND DAY OF WITHDRAWAL OF DAILY MORPHINE INJECTION (200 MG/KG) ON WATER INGESTION (LEFT SIDE) AND ALCOHOL (80% V/V) INGESTION (RIGHT SIDE) IN MORPHINE DEPENDENT RAT Z-49. COMPLETE EXPLANATION OF CUMULATIVE RECORDS IS PRESENTED IN FIGURE 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
EFFECT OF NALORPHINE INJECTIONS OF 2 MG/KG (UPPER HALF OF FIGURE) AND 4 MG/KG (LOWER HALF OF FIGURE) MADE 30 MINUTES BEFORE DRUG SESSIONS (RIGHT SIDE) ON LICKING AND LEVER PRESSING IN MORPHINE DEPNE- DENT RAT Z-44. CORRESPO fD ING PREORUG SESSIONS (LEFT SIDE) WERE OBTAI NED FOUR HOURS EARLIER, FOUR HOURS AFTER DAILY MORPHINE INJECTION (200 MG/KG). COMPLETE EXPLANATION OF CUMULATIVE RECORDS IS PRE- SENTED INFIGURE 4 ...................................... . 202
I. INTRODUCTION
Self-administration of drugs by man is not a unique phenomenon but
dates back before recorded history (Le\<1in, 1964j. To understand the
basic aspects of drug self-administration, it is essential that it be
studied in an experimental situation using experimental animals to
e1i minate the complication of psychological and ' personality factors
which complicate studies with humans.
Since Weeks (1962) described a technique for intravenous self-
administration of morphine in the rat, a considerable amount of research
has been devoted to the study of intravenous self-administration of
opiates (Thompson and Schuster, 1964), stimulants (Pickens, 1968), and
ethano 1 (Deneau et ~, 1969).
Since many drugs which are abused by man are taken orally, it was
desirable to develop a method suitable to quantitatively and reliably
measure oral self-administration of drugs in experimental animals, in
order to extrapolate the results to the human situation. Utilizing the
observation of Falk (1961) that rats trained to obtain food pellets on
a variable interval 90 second schedule, will consume three to five ·times
their normal water intake in a session when water was freely available,
Lester (l96J) reported intakes of 5.6% ethanol by rats to the point of
intoxication.
The µ·resent investigation utilized a modification of Falks (1961)
schedule induced polydipsia with operant licking chosen as the means by
which to study oral self-administration of drugs, rather than · using
lever pressing for dipper presentation of fluid. Operant licking was
chosen because it was a ' novel approach and never utilized in this way,
secondly, ingestion by licking is the way in which a rat routinely
ingests fluids.
14
1. Whether fluid acquired by operant licking would provide reliable,
quantitative data with which to study oral self-administration of
drugs by rats.
2. Whether orally ingested drugs exerted similar effects on behavior
as the same drugs injected before the session.
3. Whether chronic treatment with drugs would affect subsequent self­
administration of the same drug.
4. Whether chlorpromazine pretreatment would have any effect on
amphetamine self-ingestion.
5. Whether this system could serve as a model with which to study the
effects of disulfiram on ethanol consumption.
6. The effect of substitution of solutions of ethanol or amphetamine
for water during abstinence induced withdrawal in morphine dependent
rats.
7. The behavior of the morphine antagonist, nalorphine, on morphine
dependent rats.
II. LITERATURE SURVEY
Self-administration of drugs by man is not 3 unique · pnenomenon but
dates back before recorded history (Lewin, 1964). Drugs are used in
t\-10 ways - first for their therapeutic effect and secondly in an abusive
manner . Although the use of drugs by man precedes recorded history, the
recognition of the problem of dependence (Opioid) is a comparatively
recen t phenome non (Light and Torrence, 1929). About this same · period,
it was discovered that biological factors involved in drug dependence
could be studied in animals (Tatum~~. 1929). To place developments
in the study of dependence and self-administration of drugs in closer
perspective yet, two of the first review articles on the subject have
been j ust recently published (Schuster and Villarreal, 1967; Schuster
and Thompson, 1969).
In one of the earliest experiments which suggested that morphine
self-administration might be brought under operant control, Spragg (1940),
demons t rated that physically dependent chimpanzees, who had been deprived
of morphine, would choose a box containing a morphine-filled syringe
over a box containing food. The experimenter then injected the ani mal
with morphine. If the animal had recently received an injection of
morph i ne, it would choose the box containing food. In 1955, Headlee
et~ presented a study designed to show operant conditioning of drug
self-administration. They have also been the only investigators to use
an intr aperitoneal route of self-administration. In their study, re­
strained rats were conditioned to turn their heads laterally and inter­
rupti ng a beam of light falling on a photo-electric cell, thus starting
a· pump which infused a morphine solution through c needle inserted
through the body wall into the peritoneal cavity.
16
Weeks (1962) described a technique for intravenous self-administration
of drugs in the rat. He demonstrated clearly that rats, rendered physiol­
ogically dependent by programmed intravenous administration of morphine,
will then maintain the dependent state by pressing a lever to obtain the
drug. The self-administration technique was then extended to physically
dependent monkeys with similar results (Thompson and Schuster, 1964).
Deneau et ~ (1969) went a step further and were able to demonstrate
that monkeys v1hi ch were not phys i o 1 ogi ca lly dependent upon morphine would
initiate and maintain self-administration of morphine. These results
indicate that the monkeys developed a psychological dependence - a
preference to exist under the influence of the drug - before physiological
dependence could develop. That non-dependent monkeys will self-administer
morphine has also been confirmed by Schuster (1970).
Nichols et ~and Coppock (1956) conditioned rats to self-ingest
morphine solutions following establishment of physical dependence.
Kumar et ~ (1968) have shown it is possible to induce a preference for
morphine in rats without making them physically dependent. The method
involved makinq the rats accustomed to satisfying their normal thirst
during a limited time daily, and then substituting morphine solutions
for the water normally given.
Alcohol Self-Administration
The human disease state of 11 alcoholism11 is so complex that even
today it defies adequate description and consequently adequate therapeutic
procedures. As in most other examples of human disease, many workers have
17
attempted to develop an ani mal model for alcoholism. If such a model
for alcoholism could be developed, laboratory experimentation could be
carried out under controlled conditions, hopefully with results extrapo­
latable to the human problem. At the present time, there is a paucity
of viable studies in this area, especially of coordinated, multiparameter
studies from the same laboratory.
Factors Influencing Alcohol Consumption
Alcoholism is not a disease state endogenous to animals. Alcohol
solutions are not readily ingested by many ani mals. Despite these · pro­
blems, many investigators have looked at the factors which influence
voluntary consumption of alcohol by animals with mixed results.
(a) Physical Characteristics of the Alcohol Solution
(1) Odor-Taste - The odor and taste of solutions influence the
ingestion of alcohol by rats. For example, when ability to taste was
diminished by methylpentynol, rats were found to drink a solution of
alcohol as high as 20% (Dicker, 1958). Olfactory phenomena also seem
to have an affect, since rats made anosmic by extirpation of the olfactory
bulbs selected higher concentrations of alcohol than · prior to surgery
(Kohn and Stellar, 1960).
(2) Concentration - Rats will preferentially select a solution of
alcohol over water if the concentration of alcohol is not excessive. For
example, Myers (1968) reported that several strains of rats prefer
solutions of alcohol over water only when concentration of the solutions
are less than 7%.
(3) Caloric Content - Since solutions of alcohol are a ready
source of calories, this factor must also be considered in interpreting
18
results of alcohol ingestion. Rats have been shown to reduce their
food intake in proportion to the concentration of alcohol consumed
(Richter, 1953). However, the aversiveness of concentrations greater
than 7% was sufficient to offset the caloric value of alcohol during
severe food deprivation (Myers and Carey, 1961).
(b) Animal Factors
described in studies of alcohol consumption.
(1) Aoe - Alcohol preference was reported to be greater in young
rats (2-3 months of age) than in animals up to 2 years old (Parisella
and Pritham, 1964). However, Goodrick ( 1967) _repo.\ted that a 1coho 1
ingestion increased in rats 1-5 months old, and was greater at every
concentration in rats 24 months old as compared to rats 15 months of age.
(2) Sex .- The question of whether male or female animals drink
more alcohol has yielded results that are contradictory. Mardones (1960)
and McClearn and Rodgers (1959) reported no sex differences in alcohol
consumption by rats; Aschkenasy-Lelu (1960) and Eriksson and Malmstrom
(1967) reported that female rats consume more alcohol than males; while
Schaldewald et~ (1953), Clay (1964) and Powell et~ (1966) reported
more alcohol consumed by male than by female rats. A wide individual
variation in alcohol consumption within animals of the same strain, sex,
age etc. (Mardones, 1960 and Eriksson, 1969) has been demonstrated.
(3) Genetic Factors - By outbreeding Wistar rats which differed
in their alcohol consumption, Eriksson (1968) has raised two genetically
different lines. Marked differences between the sexes and strains were '
evident, with regard to alcohol consumption, by the eighth generation.
19
Mardones and co-workers (1953) had previously shown that a clear
correlation existed between alcohol consumption of purents and offspring.
Forsander (1967) has also demonstrated a genetic factor in alcohol
consumption.
(c) Miscellaneous Factors
In addition, there are significant effects of a variety of miscel­
laneous factors on alcohol consumption by laboratory animals.
(1) Ambient Temperature - Eriksson (1969) reported that rats
maintained at an environmental temperature of s0 c consumed more alcohol
than similar animals in environments of 22°c or 32°c. This work contra­
dicted the earlier report of Myers (1962) that rats consumed more ethanol
at 18oc than at 27°c.
(2) Effect of Pretreatment - As mentioned before, rats of several
strains will usually prefer solutions of alcohol over water if the con­
centrations are lower than 7-8% (Myers, 1968). By restricting the
animals fluid intake exclusively to solutions of alcohol, ingestion of
alcohol in concentrations up to 20% has been reported (Richter, 1953,
Mardones, 1960).
Other techniques such as injecting the animals with alcohol have
also been investigated. Myers (1963) has de~onstrated a preference for
alcohol in rats following repeated intracranial infusions of alcohol.
However, Kaz and Mende 1 son ( 1967) \'Jere unab 1 e to produce the same
phenomena in monkeys.
(3) Stress - In an attempt to increase voluntary alcohol consumption
by imposition of a stressful environment, Myers and Holman (1967) stressed
rats by intense shock given randomly around the clock for 14 days. The
20
hypothesis that an increased intake of alcohol would provide relief from
the stress was not supported ~s no increase occurred. Preference for
alcohol has been reported when a cuP. as a warning light was associated
with presentation of shock on a random basis (Cicero et ~. 1968 and
Senter and Persensky, 1968). However, the preference was only observed
during periods of stress and not afterward.
(4) Schedule - Induced Alcohol Consumption - Utilizing the
observation of Falk (1961) that rats trained to obtain food pellets on
variable intervals of 90 seconds, will consume 3-4 times their normal
water intake in a session when water was freely available, efforts have
been made to induce alcohol consumption. Using this technique, Lester
(1961) reported intakes of 5.6% alcohol solution by rats to a point of
intoxication. As with other attempts, this one also failed to create a
preference of alcohol over water (Senter and Sinclair, 1967).
(5) Nutritional Factors With regard to alcohol consumption in
self-selection experiments, it ~ust also be remembered that the choice
is not really a simple one between alcohol and water, but rather a three­
way choice in which the caloric value of alcohol can also substitute for
food (Hausmann, 1932). This situation has been recently reiterated by
Forsander (1967).
In general, forced consumption of alcohol solutions for long periods
of time has not led to an increased preference for alcohol in rats
'!
In a series of self-selection (preference) experiments, Arvola and
Forsander (1963) demonstrated a variety of species tendencies. Based
on a comparison of the percentage of alcohol in the daily fluid intake
in a choice situation of water or 10% alcohol, these authors found that
guinea pigs preferred water to an extreme, consuming about 10% of their
daily fluid as alcohol. Hamsters, on the other hand, consumed alcohol
solutions preferentially, taking in almost 90% of their daily fluid
intake as alcohol. Rats fall at an intermediate stage, with about a
30% intake.
While tolerance to alcohol has yet to be shown in rats self-ingesting
alcohol, it has been observed and measured by behavioral tasks if alcohol
is administered intragastrically. Rats trained to escape foot shock have
displayed tolerance after receiving alcohol intragastrically for a period
of time (Moskowitz and Wapner, 1964; and Chen, 1968). Tolerance, as meas­
ured by the ability of rats to run on a motor driven belt suspended over
an electrified grid, has been shown to develop maximally within three
weeks following intoxicating administration of alcohol and to be signifi­
cantly reduced after one week during which no alcohol was administered
(LeBlanc, et~. 1969).
When investigating the consumption of alcohol by rats for a length
of time, the possible development of tolerance, whether due to metabolic
changes or to cellular changes in the central nervous system (Mendelson,
1970) is an area for much needed research. More work is needed in the
area of self-ingestion as compared to involuntary administration before
the mechanism of tolerance can be clearly defined.
22
One related area of particular interest is the metabolic fate of
alcohol. While agreement exists that liver alcohol dehydrogenase is the
major enzymatic pathway for the metabolic degradation of alcohol
(Westerfeld, 1955) the exact relationship of the activity of this
enzyme to the plasma haTf-life of alcohol remains unclear. For example,
in the studies of Wilson et~ (1961), two strains of mice, the C57 Bl/6J
and C3H/Agautie were shown to have widely differing levels of liver
alcohol dehydrogenase activity. Despite this difference, the plasma
half-life of alcohol in the two strains was virtually indistinguishable
(Wilson, 1967). This correlates well with the studies of Asade and
Galambos (1963) who were unable to correlate the rate of disappearance
of alcohol from blood with liver alcohol dehydrogenase activity in humans.
Behavioral Studies
Research on the effects of alcohol on laboratory animals has the
disadvantage that one cannot ask the subjects how they feel, but on the
other hand there is much more control and flexibility in animal experi­
mentation than in human experiments. In general, the use of animal
behavioral techniques has provided some information on the effects of
alcohol.
The earliest report of the effect of alcohol on conflict behavior
was made by Masserman et~ (1944, 1945), and Masserman and Yum (1946).
Cats were first trained to obtain food and were later subjected to an air
blast or electric shock at the food, resulting in avoidance behavior.
Alcohol, injected intraperitoneally, restored the food approach behavior.­
Similar experiments have also been conducted using rats (Conger, 1951;
23
Barry and Miller, 1962; Grossman and Miller, 1961; Freed, 1967, 1968a}.
In an experi ment in which rats were induced to drink alcohol, si milar
effects were observed (Freed~ 1968b).
Experiments have given evidence that alcohol reduces frustration as
produced by extinction (Barry et~' 1962). Rats under the influence of
alcohol (injected intraperitoneally) had faster running speeds during
extinction trials (no food available) than saline treated rats.
A generalized depressant effect of alcohol was demonstrated in a
lever pressing response for water reward maintained by DRL (Differential
Reinforcement for Low Rate) schedule (Sidman, 1955; Laties and Weiss,
1962). The total number of lever presses decreased to less than half the
normal amount.
Several studies report that doses of alcohol causing ataxia are
required before there is any impairment in avoidance performance in rats
trained to avoid shock either in a shuttle box or by jumping up on a pole
(Walgren and Savolainen, 1962; Chittal and Sheth, 1963; Broadhurst and
Walgren, 1964).
Deneau et ~ (1969) demonstrated that monkeys which were not physio­
logically dependent upon alcohol would initiate and maintain self-injection
of alcohol as was also demonstrated for morphine.
Stimulant Self-Administration
Initial studies of drug self-administration by animals were concerned
with either alcohol or morphine since it was thought that only drugs which
· produce a physiological dependence in man would be self-administered by
,;
·;
induce physiological dependence but are widely abused by man. (Durrant,
1965; Connell, 1968).
The self-injection of sti mulant drugs by mo~keys was first reported
by Deneau et~ (1964). Since then, Pickens and Thompson (1968), Pickens
(1968), and Woods and Schuster (1968) have shown cocaine to be self-
administered intravenously by both rats and monkeys. Methamphetamine has
been found to be self-administered intravenously by rats (Pickens, 1968;
Pickens, Meisch and McGuire, 1967). Amphetamine was shown to be self­
administered intravenously by monkeys (Deneau et ~' 1969) and rats
(Pickens, 1968; Pickens and Harris, 1968). Nicotine has been shown to
be self-administered intravenously (Deneau and Inoki, 1967) and inhaled
as tobacco smoke by monkeys (Jarvik, 1967). A comparison between stimu­
lant self-administration and opiate self-administration has recently been
published by Thompson and Pickens (1970). Stimulant self-administration
differs from opiate self-administration in at least four respects:
acquisition of self-administration is rapid for stimulants \'Jhile very
gradual for opiates. The intervals between infusions is extremely stable
for stimulants but variable for opiates. Self-administration of stimulants
is cyclic with alternating intake and abstinence patterns while no such
pattern is observed with opiates. Finally, a long burst of responses
occurs at a very high rate during extinction of stimulant self-adminis­
tration while fo opiate extinction, responding persists at a low rate for
weeks and even months after discontinuing reinforcement.
Minor Tranquilizer Self-Administration
Recently Harris et ~ (1968) have applied operant techniques to study
25
oral self-administration of another class of drugs, the minor tranquil­
izers, in rats. In their study, drugs were used as secondary reinforcers.
Rats were initially tested for preference between water and chlordiaz­
epoxide, meprobamate, LSD, nicotinic acid and quinine. In all instances,
the rats · preferred water. The rats were then trained to lick the drug
bottle in order to obtain food reinforcement. Subsequent testing revealed
that following the association of ingestion of drug with food reinforce­
ment, the animals drank s.ignificant quantities of chlordiazepoxide,
meprobamate and nicotinic acid. The effect was not obtained with LSD or
quinine.
Subjects - Male albino-rats of Sprague-Dawley strain, random bred,
weighing between 250-300 grams at the start of the experiment, were
obtained from Charles River Breeding Farms, Wilmington, Massachusetts.
They were housed individually in an air-conditioned, light-controlled
room (lights on 12 hours - off 12 hours). Food was available ad libitum,
but water was available only for 30 minutes in the home cage, 2-4 hours
after the drug session.
Apparatus - Two animal test cages (LHV Model 1417C) housed in sound
attenuated chambers (LHV Model 1417C) were used to train and test the
rats. In each cage were two levers, a food magazine and a licking oper­
andum (Figure 1) for presentation of fluid. Each drop of fluid delivered
was 4.35 ul (Table 1). Drop size was determined by activating operandum
electrically and collecting fluid. The levers were separated by the food
magazine and licking operandum.
Drugs - Ethyl Alcohol (absolute) was obtained from U.S. Industrial
Chemicals Company, Division of National Distillers and Chemicals Corpora­
tion, New York, New York. The drugs used in this investigation were
obtained from their respective manufacturers.
Procedure
quantitatively analyzed with a free-operant technique composed of multiple
concurrent schedules (Figure 2). Responding on the left lever on a FR-5
' I
INPUT
SOLENOID
VALVE
INSULATION
Figure 1. Diagram of Licking Operandum
r r
N '1
Box - 1 Box - 2
Mean + S.E. TN) *
Grand Mean + S.E. (N)
ul/Droe
4.37 ** 0.25
Volume(ml)
** Difference between two means was non-significant (P > 0.05)
ul/Droe
4.33 ** 0.18
~Progratrmed Stimulus (llouselight On)
~ Left Lever Response ---~~=~--?-Cue (20 Second)
__ - - -CRF - - -Licking -'-~: ________________ , Fluid
Licking---------- CRF -----------)'
Food Pellet
N l.D
schedule produced 20 seconds of cue light (secondary reinforcement). Each
lick during this 20 second period was a discriminated response and pro­
vided 4.35 ul (Table 1) of fluid (primary reinforcement). Further
responses on the left lever during this 20 second period were inconsequen­
tial. Every five consecutive 20 second cue-light periods were followed
by 130 seconds of programmed stimulus not contingent upon lever pressing.
Each lick during this period also provided 4.35 ul of fluid. Left lever
· presses during this 130 second period were inconsequential. Responding
on the right lever on a FI-60 seconds schedule produced 45 mg Noyes food
pellets.
Shaping - The shaping was accomplished in the following steps:
(a) Naive, water deprived rats were placed into the training cage
and allowed to lick a drop of water which was hanging from the
licking spout. Acquisition to licking for water usually occurred
within ten minutes (Figure 3).
(b) Once rats were licking consistantly for ten minutes or more,
licking time was programmed to be contingent on left lever
pressing (FR-1). This was termed consequential licking time
and was signaled by a cue-light above the left lever. The ratio
on the Jeft lever was gradually increased to FR-5 in the same
session. Once this behavior was established, the consequential
licking time, following five responses on the left lever, was
set at 20 seconds and termed self-produced stimulus segment.
(c) A programmed stimulus segment, in which 130 second~ of continuous
cue (house light) was programmed to occur following the end of
the fifth (20 second) self-produced stimulus segment, was then
(
EXTINCTION
UJ
0:::
10MINUTES
Figure 3 .. Acquisition to licking for water in a naive rat. w _,
32
also provided 4.35 ul of fluid.
(d) Rats were shaped to press the right lever on a FI-60 second
schedule for 45 mg. Noyes Pellets by the method of successive
approximations.
Recording - Responding during each session was recorded on a Harvard
Cumulative Recorder (Gerbrands Model C-3). A typical cumulative record
of the components of the session is given in Figure 4. During the self-
· produced stimulus segment (20 seconds of cue-light following five responses
on the left lever), the fifth left lever press was recorded as a downward
deflection of the stepper pen which remained deflected for the 20 second
duration. A left lever press during the 20 second period was inconsequen­
tial and recorded as an upward deflection of the stepper pen. Licking
during the self:produced stimulus segment activated the stepper. Licking
which occurred between any of the five consecutive self-produced stimulus
segments was non-discriminated and non-consequential but also activated
the stepper pen. Discriminated licking is distinguished from non­
discriminated licking on the cumulative record in that the stepper pen
is not deflected downward before the non-discriminated licks. To
differentiate the self-produced stimulus segments from the programmed
sti mulus segments on the cumulative record, the stepper was programmed
to reset at the end of the fifth consecutive 20 second self-produced
stimulus segment. Licking during the 130 second programmed stimulus
segments also activated the stepper. Left lever presses during programm~d
stimulus were inconsequential and recorded as a downward deflection of
I r
Figure 4~ Typical cumulative record with labeled components.
w w
34
the stepper pen. To further differentiate between the two stimulus seg-
ments on the cumulative record, the event pen was in the downward position ' for the five consecutive self-produced stimulus segments and in the upward
position for the programmed stimulus segment. All right lever presses
(as no attempt was made to distinguish between consequential and inconse­
quential right lever presses on the cumulative record) were recorded as
deflections of the event pen, upward during seif-produced, and downward
during programmed stimulus segments.
In addition to the cumulative records, all responses (discriminated
and nondiscriminated) were recorded on digital counters. The cumulative
duration of each stimulus segment, self-produced and programmed, was
recorded on elapsed time meters. All recording equ1pm~nt with the exception
of the cumulative recorders was programmed to record for only the specified
length of the session to insure quantitative recording of the data. The
cumulative records were measured (30 minutes/6 inches) from the start of
the session to give the exact cumulative record corresponding to the
session.
Calculation of Response Rate - All data necessary for calculation
of response rate (responses/minute) was obtained from digital counters
and elapsed time meters. The cumulative records were used to illustrate
the pattern of responding during the sessions. Each session, unless
otherwise specified, was of 30 minutes duration. The cumulative durations
of each stimulus segment were obtained from the elapsed time meters. The
cumulative total of each response which occurred under the respective
stimulus segment was obtained from digital counters. The rate (responses/
35
minute) of each response, discriminated or nondiscriminated, was deter-
mined by dividing the total number of each response by the appropriate
cumulative value (minutes) corresponding to that portion of the ~ession
in which the response was made.
Statistical Methods - A univariate factorial analysis of variance
was performed on the data to test for significance in main effects as
treatment (drugs), dose or concentration, stimulus segment, rat and in
their interactions. A fortran computer program (MANOVA) supplied by the
Biometric Laboratory, University of Miami was used for the analyses. All
statistical analyses were performed on an I.B.M. CDC 6600 computer located
at the research computing center at Indiana University, Bloomington,
Indiana.
The students "t" test was also used to test for differences between
control and experimental groups (Dixon and Massey, 1969). The level of
significance was determined by comparison of "t" values with values from
standard tables:
Design
Predrug Session - The first of the two daily sessions was designated
as predrug session. It served two purposes: first, to determine if the
rats were behaviorally fit for the session and, secondly, it served as a
control for the drug session which followed 4-6 hours later . ....,_
Drug Session - The second daily session, following the predrug
session was designated as the drug session. An appropriate drug solution
was substituted for water for the rats to ingest during this session, or
36
the drugs were injected intraperitoneally before the session and water
was made available for licking in the training cage. The drug session
' was not run on the day a subject did not perform favorably during the
· predrug session.
Drug Studies - For each drug, a dose-response was determined with
usually six replicate sessions per dose for each rat. Three rats were
usually used in each study. The experiments performed are listed according
to the drug involved.
the experiments as follows:
Amphetamine Licking - Two Operant Schedules
Three rats, Z-29, Z-30, Z-33, were trained on two operant schedules -
licking and left lever pressing for secondary reinforcement. The
right lever was present but not programmed to deliver food pellets.
These rats were initially trained to lick for water then log concen­
trations of amphetamine (0.50, 0.99, 1.98 mM) were randomly substi-
tuted for water in the second daily sessions. Each of the concentra­
tions was presented until approximately six replicates at each
concentration were obtained.
Effect of Chronic Amphetamine Injection on Amphetamine Licking
The same three rats (Z-29, Z-30, Z-33) as used in the amphetamine
licking under two operant schedules, were injected daily . for 40 days
with a 5 mg/kg dose of amphetamine intraperitoneally four hours after
the second daily session. The following log concentrations of
37
amphetamine (0. 125, 0.25, 0.50 mM) were randomly substituted for
water in the second daily sessions during this ti me. Each of the
concentrations was presented until approximately six replicates at
each concentration were obtained. At the end of this series,
hexobarbital (130 mg/kg I.P.) sleeping time determinations were
carried out in these rats as well as in two other groups of non­
trained rats which received either daily saline or amphetamine
(5 mg/kg I.P.) injections for about 40 days also.
Effect of Chlorpromazine Pretreat men t on Amphetamine Licklr:!_g_
The effect of chlorpromazine pretreatment (0.5 mg/kg injected I.P.
30 minutes before the amphetamine session) on licking rate for
amphetamine solution was determined. For rats Z-29, Z-30 and Z-33,
the solution of amphetamine was 0.5 mM while for rats Z-50, Z-51
and Z-52, the solution of amphetamine used was 1.0 mM.
Amphetamine Licking - Three Operant Schedules
Three rats Z-34, Z-35, and Z-37 were t rained on two operant
schedules - licking and left lever pressing for secondary reinforce­
ment. In addition, they were also trained to press the right lever
to obtain 45 mg Noyes Food Pellets on a FI-60 second schedule. The
rats were initially trained to lick for water then amphetamine
--,..__ solutions (0.0625~ 0.125, 0.25, 0.50 mM) were randomly substituted
for water in the second daily sessions. Each of the concentrations
was presented until approximately six replicates at each concentra­
tion were obtained.
fffect of Amphetamine Injection on ~Jater Self-Administration
Three rats, Z-19, Z-20, Z-22 were trained on two operant schedules­
licking and left lever pressing for secondary reinforcement. The
right lever was present but not programmed to deliver food pellets.
These rats were trained to lick for water. Once trained, the rats
were injected with either normal saline (1 ml/kg,ip) or log doses
of amphetamine (0.25, 0.50, 1 .0, 2.0 mg/kg,ip) given randomly. The
injections were given 30 minutes before the second daily session
until approximately six replicates at each dose were obtained.
Ethanol - The effects of ethanol were studied in thirteen rats.
They were divided into four experiments as follows:
Ethanol Licking - Two Operant Schedules
Four rats, Z-25, Z-26, Z-27, Z-28 were trained on two operant
schedules - licking and left lever pressing for secondary reinforce­
ment. The right lever was present but not programmed to deliver
food pellets. These rats were initially trained to lick for water,
then log concentrations (10, 20, 40, 80% v/v) of ethanol were
randomly substituted for water in the second daily sessions. Each
of the concentrations were presented until approximately six repli­
cates at each concentrations were obtained.
Ethanol Licking - Three Operant Schedules
Three rats, Z-41, Z-42, Z-43 were trained on three operant schedules.
In addition to licking and left lever pressing for secondary rein­
f,orcement, the right 1 ever was a 1 so programmed on a FI-60 second
schedule to deliver Noyes 45 mg. food pellets. These rats were also
39
initially trained to lick for water, then log concentrations (5, 10,
20, 40, 80% v/v) of ethanol were randomly substituted for water in
the second daily sessions. Each of the concentrations was presented
until approximately six replicates at each concentration were
obtained.
Disulfiram Effects on Ethanol Ingestion
Three rats, Z-59, Z-60, Z-61 were trained on three operant schedules.
Once trained with water for licking, a solution of ethanol (20% v/v)
was substituted for water in the second daily session. The water
session was kept at 30 minutes but the ethanol session was increased
to 60 minutes. The rats were run for five days on ethanol before
the start of the disulfiram treatment. A suspension of disulfiram,
prepared by homogenizing the powder in 5% carboxymethylcellulose
with a drbp of tween added, was injected (50 mg/kg) intraperitoneally
60 minutes before the ethanol session. Disulfiram was injected for
six consecutive days and its effect on ethanol ingestion measured.
The rats were then run on ethanol for three more additional days
immediately after the disulfiram treatment.
Effects of Oral Ethanol Injections
Three rats, Z-53, Z-54, Z-55 were trained on three operant schedules.
A solution of ethanol (20% v/v) was given each rat~ lib in the
home cages for about 30 days. During this period a solution of
ethanol (40% v/v) was substituted for water for licking in most
of the ethanol sessions. In addition, a solution of ethanol
(50% v/v) in a dose of 12 ml/kg was injected orally 15 minutes
40
before drug sessions. Four injections were made when ethanol was
available for licking and six injections were made when water was
available for licking.
Morphine - Rats were injected with morphine according to the method
of Hikler et~' (1960). An initial dose of 10 mg/kg, I.P. was given
twice daily and increased by 10 mg increments every third day until a
total daily dose of 200 mg/kg was reached. At this time, a single daily
dose of 200 mg/kg was administered.
During the morphine dosage schedule, these rats were also trained
on the multiple-operant schedule so when they reached a dose of 200 mg/kg,
the experiments were also ready to proceed. Four rats were selected, two
(Z-44 and Z-45) were trained on two-operant schedules (no food pellets
available) and two (Z-47 and Z-49) were trained on three-operant schedules
(food pellets available).
Morphine injections were made daily, four hours prior to the first
session. The second session was run about four hours after the first
session.
Effect of Withholding Morphine Injection on Amphetamine and Ethanol Ingestion
Amphetamine Ingestion - A solution of amphetamine 0.5 m"1 was sub­
stituted for water in the second session only on the last day of
morphine injection. Responding in the behavioral box was measured
for the next four consecutive days also (when no morphine injections
were made) and then the rats were given morphine injections for at
least one day before the procedure was repeated. This procedure
41
was repeated for a total of five replicates for rats Z-44 and Z-45
and three replicates for rats Z-47 and Z-49.
Ethanol Ingestion - A solution of ethanol (80% v/v) was suostituted
for water in the second session on the last day of morphine injec­
tion for rats Z-47 and Z-49. Three, five day replicates were made
in the same way as for amphetamine ingestion.
Effect of Nalorphine Injection on ·water · Ingestion
The effect of Nalorphine 4 mg/kg, I.P., injected 60 minutes before
the second session, was determined i n rats receiving daily morphine
injections. Water was available for licking in both sessions. The
Nalorphine injection was replicated about six times in both groups
of rats Z-44, Z-45 and Z-47, Z-49.
IV. RESULTS
PREDRUG SESSIONS
As previously indicated in the experimental section, rats were run
on predrug sessions to determine whether there was any carry-over effect
of previous treatment. The decision to run a rat on any given day wa s
based on responding throughout the 30 minute session of at least 75 per­
cent of normal.
The data of predrug sessions is presented in appendices in the same
sequence data of drug sessions is presented in the results section. This
· predrug data has been analyzed by Factorial Analysis of Variance (ANOVA)
in the same way as data from drug sessions. Wherever a statistically
significant effect occurred between predrug sessions of corresponding
drug sessions, further analysis of the data was made by use of Duncans
Multiple Range Test (DMRT). The statistical significance is seen not
to occur between groups of sessions corresponding to doses or concentra­
tions in any ordered manner (successively increasing or decreasing) but
rather in a random manner indicative of variability in day-to-day
responding of the rats.
Consequential Licking
Th~ effect of ingesting amphetamine solutions of increasing
concentration~ is presented for Rat Z-19 in Figure 5. The cumulative
.
- · -- - - · .. ..__1 ·-.. . ~- - .. ··- --... - • - l ' -, I
'· . I '": , I. ~ .
' ..
Figure 5. Effect of self-ingestion of amphetamine on licking rate and lever pressing in Rat Z-19. Daily predrug (water) sessions are on left with corresponding amphetamine sessions on the right. Complete explanation of the cumulative records is presented in Figure 4 .
s
available for licking. The rates of licking were relatively
high for all the session. On the right side are the correspondiny
drug session~ where solutions of increas~ng concentrations of
amphetamine were subs.tituted for water. The licking rate as
44
well as percent of time s.pent i.n licking decreased as the concentration
of amphetamine increased to where it was almos.t totally abolished
at the highest concentration.
The effect of increasing concentrations of amphetamine solutions
on consequential licking rate in Rats Z-29, Z-30 and Z-33 is
presented graph i cally in Figure 6. These data have been presented
and analyzed in Table 2. The substitution of increasing concentrations
of amphetamine for water produced a statistically significant effect
(P < 0.001). Further analysis by DMRT showed the effect to be
concentration dependent with increasing concentrations producing
progressive decreases significantly different (P < 0.05) from '
water and with only the 1.98 and 0.99mM concentrations not
statistically different (P > 0.05) from each other under both
simulus conditions. According to ANOVA, the rats did not differ
significantly (P < 0.05) among themselves; there was no significant
effect (P > 0.05) due to stimulus condition and none of the possible
interactions showed significant relationships (P > 0.05).
As can be seen from Figure 5, the time spent in licking decreased
as increasing concentrations of amphetamine solutions were substituted
for water for Rat Z-19. According to ANOVA, time spent in licking
was significantly affected (P < 0.001) due to substitution of
amphetamine solutions for water in Rats Z-29, Z-30 and Z-33. The
data and analyses are presented in Table 3. Further analysis of
I
300
c z LLJ ~ 300 ..... ::E <{ -z 200 ~ a: 100 (.) (/)
c 0
~-· ·~·-~-·~-· .. ~? ?~ 9"" z-29 ~ z-30 "Q z-33 ?-?
PROGRAMME'D STIMULUS
·--·-~9"--. ~w-e- ~--­
L-//'--L...--L--____. 0 0.50 0.99 1.96
AMPHETAMINE ( mM)
Figure 6. Effect of amphetamine self-ingestion on consequential licking rate under self-produced and programmed stimulus in Rats Z-29, Z-30, Z-33. Clear squares represent significant differences (P < 0.05) between amphetamine sessions and corresponding predrug sessions (circles). .::::.
<.Tl
- ---- -- -- - -- ~ - ~ -- - ------ -
L:-29 L:-30 Z-3j CONC{mM} N SPS PS N -- SPS PS N sPs PS
o.o x 8 263.75 21l.75 7 295 .14 -284.43 --5- 279.00 239.00 SE 10 .93 9.78 10.94 17.76 13.07 12. 15
0 .50 x 6 159 .67 137.67 6 170 .17 162.83 7 169.29 112.43 SE 39 .43 30.57 48.57 43.93 41.15 28.16
0.99 x 5 114 .08 68.60 6 66.20 57.33 5 93.90 75.69 SE 63.58 42.06 46.47 40 .18 60 .17 42.90
l.98 x 6 23. 72 5.90 5 6.40 4.20 5 83.00 64.00 SE 8.65 5.82 2.84 3.23 59 .30 59 .13
ANALYSIS OF VARIANCE
SOURCE df MSS F CONCENTRATION ( C) -3- 368720 .43 52.62*** STIMULUS SEGMENT (S) 1 24090.65 3.44 RAT ( R) 2 1055.82 0 .15 c x s 3 79 2. 18 0 .11 C X R 6 8449. 72 . 1.20 S X R 2 3074.61 0.44 C X S X R 6 605.39 0.09 ERROR 118 7010 .40
*Significant at P < 0.05 **Significant at P < 0.01
***Significant at P < 0.001 ~ O"I
CONC
MEANS
r
1.98
37
0.99
67
0.50
136
o.oo
244
~ -.....!
(
TABLE 3
-- - -- ---- -- - ---
--- -- --
Z-29 Z-30 N SPS PS N SPS 8 7.67 9.34 7 8.67
0. 71 0. 79 0.44
6 4.84 5.79 6 5.06 0 .81 1.21 0.73
5 4.40 5.64 6 2.84 1.09 1.11 0.98
6 2.50 3.62 5 1.53 0.68 1.07 0.54
ANALYSIS OF VARIANCE
SOURCE CONttNTRATION--tC} STIMULUS SEGMENT (S) RAT c x s C X R S X R C X S X R ERROR
*Si gn-ffl cant at P **Significqnt at P
***Significant at P
118
MSS 301.41 45.48 11 .23 1.46 6.34 1.37 0.51 5.03
PS 10.32 0.62
!-3~ SPS 8.33 0.65
o.oo
9.78
Any two means not underscored by the same line ar e significantly oifferent at P <0.05.
"""' lD
50 this effect by DMRT showed, as with consequential licking rates,
there was a significant effect (P < 0.05) with increasing concentrations
of amphetamine producing progressive decreases significantly different
from water as well as between each increasing concentration with
the only exception of the 1.98 and 0.99 mM concentrations under
programmed stimulus not being statistically different (P > 0.05)
from each other. There was a statistically significant difference
(P < 0.01) between the two stimulus segments in minutes spent in
licking and it can be seen from the data of Table 3 that more
time was spent under programmed stimulus than under self-produced
stimulus. The rats did not differ significantly (P > 0.05)
among themselves in amount of time spent in licking nor were any
of the possible interactions significant (P > 0.05).
According to ANOVA, the number of reinforcements (drops of
fluid) delivered showed a statistically significant effect (P < 0.001)
when increasing concentrations of amphetamine solutions were substituted
for water. The data and analyses are present in Table 4. Further
analysis by OMRT showed the effect to be concentration dependent
with increasing concentrations producing progressive decreases
significantly different (P < 0.05) from water and from each other
with only the 1.98 and 0.99mM concentrations not statistically
different (P > 0.05) from each other under both stimulus conditions.
----There was no significant difference (P > 0.05) between the two
stimulus conditions nor among the rats. None of the possible
interactions showed any significant (P > 0.05) relationships.
I TABLE 4
OROPS OF FLUID DELIVERED DURING AMPHETAMINE SELF-INGESTION UNDER SELF-PRODUCED (SPS) AND PROGRAMMED (PS) STIMULUS IN NO~~AL RATS Z-29, 30, 33.
Z-29 z-30 Z-33 CONC(mM) _ N SPS PS N SPS PS N SPS ~
o.o x 8 2025.75 2011.75 7 2567.86 2891.86 5 2355.00 2361.20 SE 204.26 210.39 187.66 149.69 278.27 297.38
0.50 x 6 877 .00 969.00 6 957.00 1293.00 7 924.00 845.43 SE 258.45 238 .19 267.91 391.27 344.61 356. 78
0.99 x 5 472 .80 446.80 6 404.67 479. 33 5 283.80 265.40 SE 288.01 274.40 309.52 348. 16 204.44 189 .83
1.9.8 x 6 49 .33 12.83 5 23.00 18.00 5 164.20 138.80 SE 20.05 12.44 9.80 14.37 103.73 128.90
ANALYSIS OF VARIANCE
SOURCE df MSS F CONCENTRATION (C) -3- 37451363.45 102.58*** STIMULUS SEGMENT (S) l 122280.91 0.34 RAT ( R) 2 1042792.64 2.86 c x s 3 37431 .30 0.10 C X R 6 450007.75 1.23 S X R 2 186650.62 0.51 C X S X R 6 30011.83 0.08 ERROR 118 365094.20
*Significant at P < 0.05 **Significant at P < 0.01
***Significant at P < 0 .001 <.Tl
CONC
MEANS
21+07
Any two means not underscored by the same line are significantly different at P< 0.05.
01
ingested by the rats was significantly affected (P < 0.05) as
increasing concentrations of amphetamine solutions were substituted
for water. The data and analyses are presented in Table 5. Further
analysis by DMRT showed the amphetamine ingested at the highest
concentration (1.98mM) was significantly less (P < 0.05) than under
53
either of the two lesser concentrations under both stimulus conditions.
The amount of amphetamine ingested under the two lesser concentrations
(0.99 and 0.50mM) was not significant (P > 0.05) between them.
According to ANOVA, there was no significant difference (P > 0.05)
between the two stimulus conditions nor among the rats. None of the
possible interactions showed any significant relationships (P> 0.05).
Inconsequential Licking
According to ANOVA, the substitution of solutions of amphetamine
for water resulted in a significant effect (P < 0.05) on inconsequen­
tial licking rate. The data and analyses are presented in Table 6.
Further analysis by DMRT showed all concentrations produced a
significant (P < 0.05) decrease when compared to water. Increasing
concentrations of amphetamine solutions produced progressive decreases
in inconsequential licking rates, but none were significantly
different (P > 0.05) from each other. There was no significant
difference (P > 0.05) among the rats nor in the interaction between
concentrations and rats. ----
According to ANOVA, the substitution of solutions of amphetamine
for water resulted in a significant effect (P < 0.001) on consequential
( TABLE 5
DOSE OF AMPHETAMINE (MG) DELIVERED DURING SELF-INGESTION UNDER SELF-PRODUCED (SPS) AND PROGRAMMED (SP) STIMULUS IN NORMAL RATS Z-29, 30, 33.
z-=-29- -- - --~------ --- - ---z-:.10--- ---~-- ----- ---- - Z-33 CONC(mM} N SPS PS N SPS PS N SPS PS
0.0 x - - - - - - SE
0.50 x 6 1.92 2.11 6 2.08 2.81 7 2.02 1.84 SE 0.56 0.52 0.58 0.85 0.75 0.78
0.99 x 5 2.06 l.94 6 l.76 2 .16 5 1.23 1.16 SE 1.25 1.19 l.33 1.52 0.89 0.83
1.98 x 6 0.43 0.11 5 0.20 0 .16 5 1.43 1.21 SE 0 .17 0 .11 0.08 0 .13 0.90 1.12
ANALYSIS OF VARIANCE
SOURCE df MSS F CONCENTRATION (C) -r 15.57 3.71* STIMULUS SEGMENT (S) 1 0.06 0.02 RAT ( R) 2 0.40 0.10 c x s 3 0 •. 06 0.02 C X R 6 2.05 0.49 S X R 2 0.54 0. 13 ERROR 84 4.20
*Significant at P <0.05 **Significant at P <0.01
***Significqnt at P <0.001
0 . 99
1. 78
0 . 50
2 . 23
Any two means not underscored by the same line are significantly different at P~ 0 . 05 .
Vl Vl
EFFECT OF AMPHETAMINE SELF-INGESTION ON INCONSEQUENTIAL LICKING RATE UNDER SELF­ PRODUCED STIMULUS (SPS) IN NORMAL RATS Z-29, 30, 33.
Z-29- - - - --- - - z:.30 ----~----B3
CONC{mM} N SPS N SPS N SPS o.o x 8 12.38 7 17.00 --~- 16.40
SE 2.53 5.08 5.46
o .so x 6 4.50 6 3.52 7 8.14 SE 1. 71 l.08 3.79
0.99 x 5 2~00 6 2.64 5 1.16 SE 0. 71 1.47 0.57
1.98 x 6 0.62 5 3 .17 5 2 .14 SE 0.48 1.78 1.51
ANALYSIS OF VARIANCE
SOURCE df MSS F CONCENTRATION (C) -3- 723., 6 T4.4Cf*** RAT ( R) 2 18.88 0.38 C X R 6 19.58 0.39 ERROR 59 50.20
*Significant at P < 0.05 **Significant at P < 0 .01
***Significant at P < 0.001
SELF-PRODUCED STIMULUS
1. 98
o.oo 15.00
Any two means not underscored by the same line are significantly different at P <0.05.
<.J1 "'-.I
58 _left lever rate for secondary reinforcement. The data and analyses
are presented in Tabie 7. Further analysis of this effect showed all
concentrations of amphetamine solutions produced a significant
. decrease (P < 0.05) when compared to water. The consequential left
lever rate decr€ased progressively with increasing concentrations
......__
and analysis by DMRT showed the highest concentration (l.98mM )
produced a significantly lower (P < 0.05) left lever rate than the
lowest concentration (0.50mM) but the middle concentration (0.99mM)
was not significantly different (P > 0.05) from either the lowest or
highest concentrations. According to ANOVA, the rats did not differ
significantly (P > 0.05) among themselves nor was the interaction
between concentration and rats significant (P > 0.05). The effect
of amphetamine on consequential left lever rate in rats Z-29, Z-30
and Z-33 is presented graphically in Figure . 7 along with the effects
on inconsequential left lever rate under self-produced stimulus.
Inconsequential Left Lever Pressing
For Secondary Reinforcement
As can be seen from Figure 7, the substitution of solutions
of amphetamine for water resulted in a marked increase in inconsequential
left lever pressing for secondary reinforcement during self-produced
stimulus conditions. Apparently due to large variability in the
data, this effect was not statistically significant (P > 0.05)
according to ANOVA. The data and analysis are presented in Table 8.
There was a significant difference (P < 0.05) between the rates
under the two stimulus conditions and the data clearly indicates
the rates were higher under self-produced than programmed stimulus
conditions. There was no significant difference (P > 0.05) among
--- -----------
EFFECT OF AMPHETAMINE SELF-INGESTION ON CONSEQUENTIAL LEFT LEVER PRESSING FOR SECONDARY REINFORCEMENT UNDER SELF-PRODUCED STIMULUS (SPS) IN NORMAL RATS Z-29, 30' 33.
- ·------- Z-29 . Z-30 - -z~j3
CONC(mM) _ N SPS N SPS N ~ 0.0 x 8 9.17 7 12.37 5 ll.58
0.50
0.99
1.98
x 6 l.18 5 SE 0 .21
ANALYSIS OF VARIANCE
SOURCE df CONCENTRATION (C) ~ RAT (R) 2 C X R 6 ERROR 59
*Significant at P ~ 0.05 **Significant at P ~ 0.01
***Significant at P < 0.001
o.oo
10.89
Any two means not underscored by the same line are significantly different at P~ 0.05.
O'I 0
Figure 7.
8 --_J
~ (/) ..,__ wZ (/)0- 6 2 uw O"-u; 0:. w -41 (/) z z w -< 4 0:: 2 w
<( . ~ ...-- 0:: W WI > 0.. 2 w2 _J <( --
0
e 'o// o.s o.99 1.98 t;// 0.5 0.99 1.98
AMPHETAMINE (mM)
°' __,
{
EFFECT OF AMPHETAMINE SELF-INGESTION ON INCONSEQUENTIAL LEFT LEVER PRESSING FOR SECONDARY REINFORCEMENT UNDER SELF-PRODUCED (SPS) AND PROGRAMMED (PS) STIMULUS IN NORMAL RATS Z-29, 30, 33.
Z-29 ~--~-r ... ~o- ------ -- --- - --z-..:33
CONC(mM) --N 5PS PS N SPS PS N sPS PS x -0.0 8 1.81 0.44 7 0.73 0 .11 5 40.83 0.0 SE 0.38 0 .14 0.18 0.06 40.32 0.0
0.50 x 6 6.93 0.06 6 4.78 2. 18 7 1.83 0.36 SE 1.58 0.06 l.86 1.80 0.24 0 .15
0.99 x 5 7.41 0.06 6 4.35 0.31 5 5.27 1.52 SE 2.48 0.06 1.61 0.31 1.16 0.82
1.98 x 6 10. 70 1.26 5 3.97 2.07 5 1.06 0.0 SE 2.40 0.73 2.03 2.07 0. 71 0.0
ANALYSIS OF VARIANCE
SOURCE df MSS F CONCENTRATION (C) -3- 88.33 0. 31 STIMULUS SEGMENT (S) l 1350.64 4. 77* RAT ( R) 2 160.50 0.57 c x s 3 129. 90 0.46 C X R 6 458.45 1.62 S X R 2 213. 35 0.75 C X S X R 6 446.25 1.57 ERROR 118 284.94
*Significant at P < 0.05 **Significant at P ~ 0.01
***Significant at P < 0.001 0) N
CONC
MEANS
I
0.50
4.37
1. 98
1 • 12
Any two means not underscored by the same line are s ignificantly different at P< 0.05.
O'I w
the rats nor did any of the possible interactior.s show significant
relationships (P > 0.05}.
Effect of Chronic Amphetam ine Injection on Amphetamine Licking I
The same three rats Z29, Z-30 and Z-33 as used in the previous
experiment to determine the effects of amp hetamine self-ingestion
were used to determine the effects of a daily intraperitonea1
injection of amphetamine (Smg/kg) given four hours after the daily
amphetamine lick i ng sessions. On days prior to the start of the
experiment, these rats were also injected daily with 5mg/kg of
amphetamine.
on consequential li cking rate in these amphetamine treated rats
is presented graph ically in Figure 8. Increasing concentrations
produced decreased Ticki ng rates, but the major difference between
this experiment and the previous one was that concentrations required
were considerabl y lower; 0.125, 0.25 and O.SOmM versus 0.50, 0.99
and 1.98mM of t he previous experiment. A comparison of these resu]ts
is presented graphically in Figure 9. According to ANOVA, the licking
rates were signifi cantly affected (P < 0.001) when increasing I
concentrations of amphetamine solutions were substituted for water.
The data and anal yses are presented in Table 9. Further analysis
by DMRT showed that licki ng rates under all concentrations of
amphetamine were sign i f i cantly decreased (P < 0.05) when compared to
water. Under sel f -produced stimulus, the licking rates were not
significantly different (P > 0.05) under any of the amphetamine
(
~- z 300
i--i-i-i ~i-•-· 1-•-•-i '---o---o ~
~'i' ___-Q'--..:_ 'i'-r-~ If
'i' Q~ ~-------'i'~ ""r-i'--r ? 't '!
L II I I I L// I I I LI! I I I 0 0.125 Q25 Q50 0 0.125 0.25 Q50 0 0,125 0.25 Q50
AMPHETAMINE (m M)
i
Figure 8. Effect of amphetamine self-ingestion on consequential licking rate under self-produced and programmed stimulus in rats Z-29, Z-30, Z-33 which were chronically i~ected with 5 mg/kg, i.p. of amphetamine, 4 ho~rs after the amphetamine session. Clear squares represent significant difference (P < 0.05) between amphetamine and corres ponding predrug sessions (circles).
O"I (J1
~
0 0
Ll-J Z-33
PROGRAMMED STIMULUS
125 .25 .50 .99 1.98 .125 .25 .50 .99 1.98 .125 .25 .50 .99 1.98 AMPHETAMINE (mM)
°' °'
CONC{mM} 0.0 x
0.25 x SE
0.50 x SE
Z- 9 ~--- -z-·3·0 N SPS PS N SPS PS
-7- 241. 5 7 247.00 -6- 245.67 22 8 . 17 17.54 26.61 7.05 8.24
7 206.29 153.43 7 79.00 80.29 7.86 24.93 37.56 38.70
5 203.00 162.40 6 121.33 146. 17 11. 80 16.94 27.35 33.81
7 95.29 77. 14 6 60,50 58.67 45.28 40.39 28.84 3 7. 11
ANALYSIS OF VARIANCE
SOURCE CONCENTRATION (CJ STIMULUS SEGMENT (S) RAT (R) c x s C X R S X R C X S X R ERROR
* s i g n i f 1 c a n t a t P < 0 . 0-5 **Significant at P < 0.01
***Significant at P < 0.001
126
Z-33 N S PS
·----p-s 238.80
19. 66
100.38 38.78
130.50 34.22
104.67 42.69
0.80
238
Any two means not underscored by the same line are significantly different at P< 0.05.
°' (X)
difference (P < 0.05) occurred between the 0.125 and 0.25mM concen­
trations. According to ANOVA, there was no significant difference
(P > 0.05) between the stimulus conditions and the rats differed
significantly (P < 0.05) among themselves. None of the possible
interactions showed any significant relationships (P > 0.05).
69
According to ANOVA, the substitution of increasing concentrations
of amphetamine for water resulted in a significant effect (P < 0.001)
on the amount of time spent in licking. The data and analyses are
presented in Table 10. Further analysis of this effect by DMRT
showed that the amount of time spent in licking under either stimulus
condition was significantly reduced (P < 0.05) when compared to water.
Under both stimulus conditions, the amount of time spent in licking
at the 0.50mM concentration of amphetamine was significantly less
(P < 0.05) than at the 0.25mM concentration. The O.l25mM concen­
tration effect was not significantly different (P > 0.05) from the
other two. According to ANOVA, there was a significant difference
(P < 0.05) between the two stimulus conditions and data of Table 10
indicates more time was spent in licking under the programmed stimulus
than the self-produced stimulus. The rats differed significantly
(P < 0.01) among themselves and the interaction between concentration
and rats showed a significant (P < 0.01) relationship. A graphical
comparison of time spent in licking by these rats during the
experiment prior to the one in which they received daily injections
of amphetamine is presented in Figure 10. Although the concentrations
used for licking were considerably lower, the amount of time spent
in licking was also generally less when the rats were receiving
I TABLE 10
EFFECT OF AMPHETAMINE SELF-INGESTION ON TIME IN MINUTES SPENT IN CONSEQUENTIAL LICKING UNDER SELF-PRODUCED(SPS) AND PROGRAMMED(PS) STIMULUS IN CHRON!CALLY INJECTED RATS Z-29,30,33.
Z-29 Z-30 Z-33 CONC(mM) N SPS PS N SPS PS N SPS PS
0.0 x - 7- 11 . 2 7 12. 1 8 - 6- ,, . 35 13.70 -5- l 1. 66 13.77 SE 0.50 0.96 0.50 0.46 0.38 0.40
0. 12 5 x 7 6.23 7.44 7 3.80 4.25 7 3. 1 7 3.41 SE 0.90 0.93 1. 46 1. 89 0.90 1. 41
0.25 x 5 6.33 7. 81 6 5.46 6. 51 6 3.66 4.55 SE O". 64 0.87 1. 06 1. 2 5 0.64 0.92
0.50 x 7 3.52 3.41 6 1. 44 1. 81 6 3.89 5.06 SE 1 . 1 4 1. 49 0.77 1. 18 0.96 1. 33
ANALYSIS OF VARIANCE
SOURCE df MSS F C-0 NC E N T RAT I 0 N ( c) -3- 580.88 79.13*** STIMULUS SEGMENT (S) 1 34.48 4.70* RAT ( R) 2 35.43 4.83** c x s 3 3.05 0.42 C X R 6 26.30 3.58** S X R 2 0. 1 8 0.02 C X S X R 6 1. 41 0. 19 ERROR 126 7.34
*Significant at P< 0.05 **Significant at P < 0.01
***Significant at P < 0.001 -...J 0
CONG
MEANS
I .
0.50
2.98
13. 13
...... __.
(9 6.0 z :x:: u 4.0 ::i
2.0 z -G) I- . 0 Z\/) w., BJ~ 8.0 \/)Lu w66.0 I­ => z 4.0 2:
2.0
0
~ ~
:t~5 2 1 5 5o g'g 1.00 .125 .25 .50 .99 t98 :125 .25 .so .99 1.00
AMPHETAMINE (m M)
\ .
According to ANOVAs the substitution of increasing concentrations
of amphetamine for water resulted in a significant effect (P < 0.05)
on the milligrams of amphetamine sulfate ingested by the rats. The
data and analyses are presented in Table 11. Further analysis of
this effect by DMRT showed progressively